Rifaximin is a semisynthetic derivative of rifamycin, wherein rifaximin is an oral, bactericidal broad-spectrum antibiotic. The IUPAC name of rifaximin is (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S,28E)-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypenta-deca[1,11,13]trienimino) benzofuro[4,5-e]pyrido[1,2-a]-benzimida-zole-1,15(2H)-dione,25-acetate and the compound is represented by the following formula

Rifaximin can be used in the treatment of bacterial infections of the gastrointestinal tract, for example in the treatment of traveler's diarrhea. Further, the active pharmaceutical agent can be used in the treatment or prevention of hepatic encephalopathy and is said to be efficacious in relieving chronic functional symptoms of bloating and flatulence that are common in irritable bowel syndrome (IBS) and Morbus Crohn.
Rifaximin is reported to show its efficiency almost exclusively locally, i.e. rifaximin exerts its effects at the site of application, wherein this site of application is the gastrointestinal tract.
Several polymorphic forms of rifaximin are described, wherein these polymorphic forms can convert into each other. Viscomi G. C. et al., “Crystal forms of rifaximin and their effect on pharmaceutical properties”, Royal Society of Chemistry, CrystEngComm, 10 (2008), pages 1074-1081, show in FIG. 4 a diagram in which the relationship between the various polymorphic forms of rifaximin is scheduled. The conversion of these different forms into each other inter alia seems to be related to the amount of moisture, in particular water, contained in the corresponding forms. As can be seen from Table 7 of said document, the bioavailabilities of the various forms of rifaximin differ from each other. For example, with reference to the corresponding Cmax and AUC values, rifaximin in form γ or in form δ are reported to show a far higher bioavailability (in dogs) than rifaximin in the other polymorphic forms:
FormCmax [ng/ml]AUC [ng/ml × h]Alpha2.617Beta1.112Gamma1,085.14,894Delta308.3830Epsilon6.977
With reference to the above-mentioned local effectiveness of rifaximin, a low bioavailability is desirable. As can be seen from the above-mentioned table, rifaximin in polymorphic forms β and ε are reported to show a rather poor bioavailability. However, form β of rifaximin is reported to contain water in an amount of 6 to 40 wt %. Drugs having such a high water content are usually regarded as disadvantageous since they usually have inferior stability and processability properties. Further, it is difficult to prepare form ε of rifaximin since it is reported to be obtained only under very specific conditions.
Further, Blandizzi C. et al., “Impact of crystal polymorphism on the systemic bioavailability of rifaximin, an antibiotic acting locally in the gastrointestinal tract, in healthy volunteers”, Drug Design, Development and Therapy, 9 (2015) pages 1-11, compare the bioavailability of rifaximin in a human after the administration of rifaximin in amorphous form and rifaximin in polymorphic form α, each in the amounts of 200 mg and 400 mg. In table 2 of said document it is shown that the Cmax value and AUC values are significantly higher when rifaximin in amorphous form is administered:
DosageCmax [ng/ml]AUC [ng/ml × h]200 mg amorphous3.7016.13200 mg alpha1.595.77400 mg amorphous15.0168.80400 mg alpha3.5413.03
In view of the above, due to the reaction mechanism of rifaximin, there is still a need of a pharmaceutical composition containing rifaximin with a bioavailability being as low as possible. Hence, it was an object of the present invention to overcome the drawbacks of the above-mentioned prior art.
In particular, it was an object of the present invention to provide a pharmaceutical composition containing rifaximin showing minimal Cmax and AUC values while at the same time achieving a sufficient local concentration in the gastrointestinal tract. Further, it was an object to provide a pharmaceutical composition containing rifaximin wherein the minimal Cmax and AUC values can be achieved even after storage of the pharmaceutical composition. In addition, a pharmaceutical composition with good processability should be provided, i.e. the pharmaceutical composition should be processed into an oral dosage form, preferably a tablet, without the need of a time and cost-consuming preparation method.
According to the present invention, the above objectives are unexpectedly achieved by a pharmaceutical composition comprising two specific polymorphic forms of rifaximin being present in a specific molar ratio.
Thus, a subject of the invention is a pharmaceutical composition comprising                (A) rifaximin in polymorphic form α,        (D) rifaximin in polymorphic form δ,wherein the molar ratio of (A) rifaximin in polymorphic form α to (D) rifaximin in polymorphic form δ is from 9:1 to 1:9.        
A further subject of the invention is the method for preparing a tablet according to the present invention comprising the steps of    (i) providing (A) rifaximin in polymorphic form α and (D) rifaximin in polymorphic form δ, wherein the molar ratio of (A) rifaximin in polymorphic form α to (D) rifaximin in polymorphic form δ is from 9:1 to 1:9 and optionally one or more further excipients    (ii) optionally dry granulating the mixture of step (i) and optionally one or more further excipients    (iii) compressing the mixture from step (i) or the granulates from step (ii) and optionally further excipients into a tablet.
It was unexpectedly found that the pharmaceutical composition of the present invention containing rifaximin in polymorphic forms α and δ in a specific molar ratio shows an advantageously low Cmax value. Thus, a reliable and poor systemic absorbance of the active pharmaceutical ingredient is achieved. The achieved Cmax value is even lower than the one of rifaximin in pure polymorphic form α. Further, the pharmaceutical composition of the present invention is easy to handle and can for example be further processed by direct compression into a tablet.